2.5 Targeted Therapies, Immunotherapies, & CAR-T Cell Therapy

2.5 Targeted Therapies, Immunotherapies, & CAR-T Cell Therapy

Cancer therapeutics have evolved beyond traditional non-specific cytotoxic chemotherapy toward targeted agents and immunotherapies. Targeted therapies inhibit specific molecular drivers of malignant transformation, while immunotherapies harness the host's immune system to recognize and eliminate cancer cells. Despite improved target specificity, these novel agents induce unique, mechanism-based toxicities that require specialized medical nutrition management.

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Targeted Therapies: Monoclonal Antibodies & Small Molecules

1. Monoclonal Antibodies (mAbs)

Monoclonal antibodies are engineered proteins designed to bind specific extracellular tumor antigens or receptor tyrosine kinases.

2. Tyrosine Kinase Inhibitors (TKIs)

TKIs are orally bioavailable small-molecule inhibitors that enter target cells and bind to the ATP-binding pocket of intracellular tyrosine kinase domains, blocking downstream signal transduction.

• Imatinib: Inhibits BCR-ABL (Philadelphia chromosome in CML) and c-KIT (Gastrointestinal Stromal Tumors [GIST]). Toxicities include periorbital edema, fluid retention, nausea, diarrhea, and muscle cramps. MNT: Take with meals and a large glass of water to minimize GI irritation.
• Erlotinib / Osimertinib: Inhibits EGFR kinase in non-small cell lung cancer (NSCLC). Toxicities include severe diarrhea, stomatitis, and anorexia.
• Drug-Food Interactions (CYP3A4 Inhibition): Most oral TKIs are metabolized by hepatic CYP3A4 enzymes. Co-ingestion of grapefruit, grapefruit juice, Seville oranges, or starfruit inhibits CYP3A4, causing toxic systemic TKI drug accumulation. Conversely, St. John's Wort induces CYP3A4, reducing TKI efficacy.

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Immune Checkpoint Inhibitors (ICIs) & irAEs

Immune Checkpoint Inhibitors block inhibitory signaling pathways (checkpoints) that tumors exploit to evade T-cell mediated destruction.

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|                                IMMUNE CHECKPOINT INHIBITOR CLASSES                                      |
| 1. PD-1 Inhibitors:    Pembrolizumab, Nivolumab (bind PD-1 receptor on T-cells).                        |
| 2. PD-L1 Inhibitors:   Atezolizumab, Durvalumab (bind PD-L1 ligand on tumor cells).                     |
| 3. CTLA-4 Inhibitors:  Ipilimumab (binds CTLA-4 on T-cells to enhance early T-cell activation).          |
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Immune-Related Adverse Events (irAEs)

Unbraking T-cell activity can cause autoimmune tissue destruction across any organ system, termed immune-related adverse events (irAEs).

• Immune-Mediated Colitis & Diarrhea: Most frequent severe GI irAE (common with ipilimumab or combination PD-1/CTLA-4 blockade). Manifests as severe watery diarrhea (>6 stools/day above baseline), abdominal pain, hematochezia, and mucosal ulceration on colonoscopy.
  • Management: Rule out infectious etiologies (C. difficile, CMV). Grade 1: Symptomatic anti-motility therapy. Grade 2–4: Immediate holding of ICI and high-dose systemic corticosteroids (prednisone 1–2 mg/kg/day or IV methylprednisolone). If refractory: Infliximab (anti-TNF alpha) or Vedolizumab.
  • MNT: Low-residue, low-fat, lactose-free diet; aggressive electrolyte repletion; parenteral nutrition if corticosteroid-refractory severe colitis requires prolonged bowel rest.
• Endocrinopathies: Autoimmune hypophysitis, thyroiditis (primary hypothyroidism or hyperthyroidism), and autoimmune Type 1 Diabetes Mellitus. MNT: Monitor thyroid panel (TSH, free T4) and blood glucose; initiate levothyroxine or insulin as indicated.

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CAR-T Cell Therapy: CRS & ICANS

Chimeric Antigen Receptor (CAR) T-Cell Therapy is an autologous cellular immunotherapy. Patient T-cells are harvested via leukapheresis, genetically engineered via viral vectors to express a CAR targeting a specific tumor antigen (e.g., CD19 in B-cell ALL/lymphoma or BCMA in Multiple Myeloma), expanded ex vivo, and re-infused into the patient following lymphodepleting chemotherapy (fludarabine + cyclophosphamide).

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|                                 CAR-T CELL THERAPY WORKFLOW                                             |
| Leukapheresis -> T-Cell Isolation -> CAR Gene Transduction -> Ex Vivo Expansion -> Lymphodepletion      |
| -> Infusion of CAR-T Cells -> In Vivo Expansion -> Targeted Tumor Lysis + Cytokine Surge               |
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1. Cytokine Release Syndrome (CRS)

As infused CAR-T cells encounter target tumor antigens, they undergo massive in vivo clonal expansion and release immense quantities of inflammatory cytokines—specifically Interleukin-6 (IL-6), Interferon-gamma (IFN-g), and Tumor Necrosis Factor-alpha (TNF-a).

2. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

ICANS is a neuropsychiatric toxicity caused by cytokine-mediated blood-brain barrier disruption and central nervous system inflammation. Manifestations include expressive aphasia (loss of speech fluency; early pathognomonic sign), dysgraphia (inability to write), tremors, confusion, seizures, and cerebral edema.

• Clinical Assessment: Evaluated daily using the ICE (Immune Effector Cell Encephalopathy) score (evaluating orientation, naming, writing, following commands).
• Management: High-dose IV dexamethasone; seizure prophylaxis (levetiracetam); continuous neurological monitoring. MNT: Maintain enteral nutrition access (nasogastric/nasojejunal tube) if dysphagia or encephalopathy impairs safe oral swallowing.